In this Partners SPOTRIAS renewal application, we propose three highly innovative stroke studies. Two are clinical trials, a phase II safety study to expand the use of tPA to patients lacking a clear stroke onset time using the MRI signature to predict time of onset, and a translational study which culminates in a Phase 1B trial of a novel therapeutic approach, ROCK inhibition with SLx-2119. Both studies build upon translational preclinical and imaging studies performed at the MGH and BWH. The third project is an fMRI recovery project, which is being performed in collaboration with Columbia University. These unique projects seek to expand the use of acute stroke therapies and improve prediction of outcome. We have applied to renew the four requisite Cores, and an optional Neuroimaging Core from our first SPOTRIAS cycle. The Access and Administrative Core (Core A) leverages the considerable clinical resources at Partners to treat acute stroke patients with thrombolytic therapy as rapidly as possible, and enroll subjects in SPOTRIAS projects. The Neuroimaging Core (Core B) has established mechanisms for standardized imaging data retrieval, analysis, and archiving. The Blood and Tissue Core (Core C) will support blood sample collection and processing for Project 2 and SPOTRIAS plasma repository sample submission. The Biostatistics and Data Management Core (Core D) will continue to provide state-of-the- art support for the SPOTRIAS projects to ensure high quality data and statistical analyses. In addition, we have added a new, discrete Training Core (Core E) as part of this submission. This new Core will strengthen the integration between the clinical and research acute stroke fellowships and coordinate the training experience for the SPOTRIAS fellows. RELEVANCE: Stroke poses a major health burden on the population of the United States. With only one approved acute stroke therapy (intravenous tPA), and limited use of that treatment, there is a dire need for additional translational research to develop new therapeutic approaches and novel paradigms for the delivery of acute stroke care. 2P50NS051343-06/Project 1 Schwamm, Lee DESCRIPTION (provided by applicant): Despite significant progress in stroke prevention and its acute treatment, stroke remains the third leading cause of death and a leading cause of adult morbidity worldwide. By defining "stroke symptom onset" in the most conservative manner, namely the time the patient was last seen well, many patients whose onset is unwitnessed are automatically ineligible for thrombolytic therapy even if their true time of onset would allow them to qualify. If a technique existed that could replace the human witness and testify that the stroke was in fact less than 3.5 hours duration, then these patients could be considered for alteplase treatment under current American Heart Association (AHA) guidelines, and be treated if eligible according to the inclusion and exclusion criteria. Many stroke patients are rapidly brought to the hospital within 3 hours of the time of symptom discovery, but FDA indications exclude them from consideration for intravenous alteplase if it has been greater than 3 hours since the time they were last known to be well. We propose to use advanced MR imaging as the "witness" to testify as to stroke duration in those patients who do not have a human witness in an open label Phase Ha safety study of thrombolysis in these patients. We have modeled the other eligibility criteria after the ECASS3 trial design and the current AHA guidelines in order to limit the variable of interest to the use of MR as the determinant of time of stroke onset. We will exclude patients from the study who arrive within 3 hours from last seen well since these patients are eligible for on-label treatment with thrombolysis. Because the study is open-label and investigators are unblinded, we will use the more conservative ECASS-2 definition of symptomatic ICH. This is defined as any hemorrhage with neurologic deterioration, as indicated by an NIHSS score that was higher by 4 points or more than the value at baseline or the lowest value in the first 7 days or any hemorrhage leading to death, and does not require that the ICH be classified as causally linked to the neurologic deterioration. If our study is successful, we can potentially expand use of lytics to a stroke patient population for whom little acute intervention is currently offered. PUBLIC HEALTH RELEVANCE: Stroke is a leading cause of death and morbidity in the US. Thrombolysis is approved by the FDA for treatment within 180 minutes from when a patient was last seen well. Approximately 25% of stroke patients have unwitnessed onset times. This study seeks to expand IV thrombolysis to these patients using neuroimaging as the "witness" to establish the stroke duration when a human witness is unavailable.